Genetics

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Genetics

Postby dignan » Fri Jan 26, 2007 10:53 am

Interesting genetics of MS study. I expect Bromley might have something to say about this as I think part of his personal team of world-leading neurologists is involved...



A second major histocompatibility complex susceptibility locus for multiple sclerosis.

Ann Neurol. 2007 Jan 24; [Epub ahead of print]
Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A, Fenoglio C, Ban M, Taylor CJ, Goodman RS, Walsh E, Wolfish CS, Horton R, Traherne J, Beck S, Trowsdale J, Caillier SJ, Ivinson AJ, Green T, Pobywajlo S, Lander ES, Pericak-Vance MA, Haines JL, Daly MJ, Oksenberg JR, Hauser SL, Compston A, Hafler DA, Rioux JD, Sawcer S.
Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.

OBJECTIVE: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.

METHODS: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.

RESULTS: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)).

INTERPRETATION: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.

Pubmed reference
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Postby gwa » Fri Jan 26, 2007 11:54 am

I would like for biodoc to interpret this.

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Postby BioDocFL » Fri Jan 26, 2007 4:26 pm

gwa,

I think wikipedia.org (key in: major histocompatibility complex) can give a better explanation than me so check it out. MHC and HLA are related and often used somewhat interchangeably. MHC tends to be the big complex, HLA tends to refer to components.

The MHC proteins encoded by these genes serve to display antigens on the surface of a cell so that marauding T cells can investigate what material is in the area, good or bad. When a cell presents an antigen in the grasp of an MHC molecule, the T cell is presented with something normal (the MHC protein) and recognizable as 'self' and something that is possibly not normal (the antigen in the grasp of the MHC). The antigen could be a fragment from a digested protein that originated from the cell itself, or it could be a fragment of a bacterial protein or viral protein. It could also be other types of material like DNA, but usually we think of protein fragments being displayed. If the T cell does not consider the antigen as a danger, it will eventually move on. If it is interpreted as foreign, the T cell can become activated to start an attack on the cell.

The different genes for the MHC complex encode different protein components of the MHC complex. Each component can use a different subclass, depending on the individual. People who have the HLA-DRB1 type for the HLA-D subclass seem to have a higher susceptibility for autoimmune disorders. The difference in their DNA sequence appears to have been located at base 1501 in the gene it appears. A change in a DNA base can alter the amino acid that is encoded so that the protein has a slightly different amino acid sequence. This can alter the shape of the antigen binding site of the protein, allowing some indiscretion as to what it accepts in size and shape of antigen displayed, or perhaps the amino acid change allows a different charge there so it can be more or less sticky in holding antigens. But somehow it is thought to allow some improper displaying of antigens in the MHC complex. Perhaps something that is normally internal in the cell is now being displayed as if it is foreign and from outside of the cell. Different classes of MHC complexes are involved in displaying material that originated internally versus externally. So indiscretion by the MHC could confuse the T cell inspecting it and its antigen.
So HLA-DRB1 with its sequence difference has been recognized. There are other MHC related genes that the authors studied to see if they have a relation to MS susceptibility besides the HLA-DRB1 gene. And it appears that HLA-C genes have some sequence changes that could also, (and perhaps independent of HLA-DRB1 changes) lead to susceptibility.
That's my interpretation of their report just from the abstract. This type of work, if proven, could allow us to identify people earlier who have a susceptibility. Previously we might have only been looking for the HLA-DRB1 subclass but this suggests that we should check for HLA-C subclass genes too as an independent parameter.
Hope that helps. Late night at the office. It's Friday and time for me to go home.

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Thanks

Postby gwa » Sat Jan 27, 2007 2:51 pm

Wesley,

Thanks for the explanation. It does help.

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